1-phenylbenzimidazole-2-methanol



United States Patent 3,431,274 1-PHENYLBENZIMIDAZOLE-2-METHANOL John W.Schulenberg, Bethlehem, N.Y., assignor to Sterling Drug Inc., New York,N .Y., a corporation of Delaware No Drawing. Continuation-impart ofapplication Ser. No.

588,339, Oct. 21, 1966, which is a continuation-inpart of applicationSer. No. 404,952, Oct. 19, 1964. This application Mar. 29, 1968, Ser.No. 717,404 US. Cl. 260--309.2 1 Claim Int. Cl. C07d 49/38 ABSTRACT OFTHE DISCLOSURE 1-R-2-R-benzimidazole 3-oxides, where R and R arelower-alkyl or phenyl, at least one of R and R being phenyl, havinghyperglycemic and tranquillizing activities, are prepared byhydrogenating the appropriate Z-nitroanilines substituted on nitrogen bythe groups R and COR", where R" is lower-alkyl, phenyl,l-chloro-lower-alkyl or l,l-dichloro-lower-alkyl. Also disclosed isl-phenylbenzimidazole-Z-methanol, having bacteriostatic properties.

This application is a continuation-in-part of application Ser. No.588,339, filed Oct. 21, 1966, now US. Patent 3,415,839, which is in turna continuation-in-part of application Ser. No. 404,952, filed Oct. 19,1964, now abancloned.

This invention relates to new heterocyclic compounds and in particularis concerned with 1,2-disubstituted-benzimidazole 3-oxides and thepreparation thereof, including intermediates therein.

The compounds of the invention are of the following structure:

0 T N C-R' R wherein R and R are lower-alkyl or phenyl, at least one ofR and R being phenyl. The lower-alkyl group preferably has from one tofive carbon atoms.

The substitution of simple moieties on the benzene ring of thebenzimidazole nucleus, and/ or on the groups R and R when they stand forphenyl does not adversely affect the pharmacological activity of thecompounds and such substituted compounds are the full equivalents of thecompositions herein claimed. Illustrative but not limitative examples ofsuch simple moieties are lower-alkyl, lower-alkoxy and halo.

The compounds of the invention are prepared by catalyticallyhydrogenating a compound of the formula wherein R is lower-alkyl orphenyl, and R is loWer-alkyl, l-chloro-lower-alkyl,1,1-dichloro-lower-alkyl or phenyl, at least one of R and R" beingphenyl. Preferred catalysts are platinum oxide and palladium-on-carbon.The compounds of Formula II are in turn prepared by reacting a2-nitro-N-'(R)-aniline with the appropriate alkanoyl halide, R"-COX,Where X is chlorine or bromine. Compounds bearing substituents in thebenzene rings are prepared by the same process.

A further aspect of the invention lies in novel intermediates of theformula N-C OR phenyl III chomotor depressant properties thus indicatingtheir usefulness in regulating the blood sugar content and astransquillizers.

The compounds of Formula I are useful both in free base form and inacid-addition salt form, and both forms are within the purview of theinvention and are considered to be one and the same invention.

The following examples will further illustrate the invention.

EXAMPLE 1 (a) N ehloroacetyl-2-nitrodiphenylamine [111; R" is CH CIJ: Amixture of 64.2 g. (0.3 mole) of 2-nitrodiphenylamine, 67.5 g. (45 ml.,0.6 mole) of chloroacetyl chloride and ml. of toluene was refluxed forfour and three-quarters hours. The toluene was removed in vacuo and theresidue recrystallized from ethanol to give 74.5 g. ofN-chloroacetyl-2-nitrodiphenylamine, yellow prisms, M.P. 122-124 C.(uncorr.); ultraviolet maximum at 232 m (e=16,300); infrared absorptionpeak at 5.91 4.

N-chloroacetyl 2 nitrodiphenylamine when administered intraperitoneallyto mice at a dose level of 100 mg./ kg. showed an 82% decrease inspontaneous activity.

By replacing the chloroacetyl chloride in the preceding preparation by amolar equivalent amount of u-chloropropionyl chloride,a-chloroisobutyryl chloride or oz-ChlO- rocaproyl chloride, there can beobtained, respectively, N-(a-chl-oropropionyl) 2 nitrodiphenylamine,N-(achloroisobutyryl)-2-nitrodiphenylamine, or. N-(Ot'ChkJl'O-caproyl)-2-nitrodiphenylamine.

By replacing the 2-nitrodiphenylamine in the preceding preparation by amolar equivalent amount of 2-nitro-4- methyldiphenylamine, there can beobtained N-chloroacetyl-2-nitro-4'methyldiphenylamine.

(b) 1-phenyl-Z-methylbenzimidazole 3-oxide ['I; R is C H R is CH Asolution of 14.55 g. (0.05 mole) of N-chloroacetyl-2-nitrodiphenylaminein 225 ml. of absolute ethanol was hydrogenated at room temperature inthe presence of 200 mg. of platinum oxide. After one hour the requisitethree molar equivalents of hydrogen had been absorbed, and thehydrogenation was terminated and the mixture filtered. The hydrogenationwas repeated starting with 13.0 g. ofN-chlloroacetyl-Z-nitrodiphenylamine, and the two runs were combined andconcentrated to a small volume. The product was crystallized fromacetone containing .a little absolute ether to give 17.0 g. ofl-phenyl-Z-methylbenzimidazole 3-oxide in the form of its hydrochloridesalt, prisms, M.P. 2120-2136 C. (dec.) (corn); ultraviolet maxima at249, 272 and 279 m (6:6080, 7300 and 7700, respectively), and shoulderat 289 mu; infrared absorption peaks at 3.30, 4.50, 6.22, 6.28, 6.60,6.71, 6.85, 7.34, 7.57, 7.98 and 8.17 1.

Analysis.-Calcd. for C H N O-HCI: C, 64.49; H, 5.02; N, 10.75. Found: C,64.79; H, 4.99; N, 10.61.

1-phenyl-2-methylbenzimidazole 3-oxide was also obtained whenN-chloroacetyl-Z-nitrodiphenylamine was hydrogenated in the presence ofpalladiumon-carbon catalyst instead of platinum oxide catalyst.

A sample of the hydrochloride salt was dissolved in water, excesspotassium bicarbonate added, and the base extracted with chloroform. Thechloroform extracts were washed with water, dried and concentrated, andthe residue recrystallized from ethyl acetate to give 1-phenyl-2-methylbenzimidazole 3-oxide in the form of colorless prisms, M.P.159-167 C. (uncorr.); infrared absorption peaks at 3.32, 6.28, 6.64,6.83, 7.35, 7.70, 8.03 and 8.24 1.

Analysis.Calcd. for C H N O: C, 74.99, H, 5.38; N, 12.49. Found: C,75.42; H, 5.14; N, 12.39.

By replacing the N-chloroacetyl-Z-nitrodiphenylamine in preparation (b)above by a molar equivalent amount of N-(a-chloropropionyl) 2nitrodiphenylamine, N- (a-chloroisobutyryl) 2 nitrodiphenylamine, N(achlorocaproyl) 2 nitrodiphenylarnine, or Nchloroacetyl-2-nitro-4'-methyldiphenylamine, there can be prepared,respectively, 1-phenyl-2-ethylbenzimidazole 3-oxide,l-phenyl-2-isopropylbenzimidazole 3-oxide, l-phenyl-2-pentylbenzimidazole 3-oxide, or 1-(p-tolyl)-2-rnethylbenzimidazole3-oxide.

1-phenyl-2methylbenzimidazole 3-oxide in the form of its hydrochloridesalt when administered at 100 mg./kg. orally to fasted male rats causeda 49% increase in the blood glucose level.

1-phenylbenzimidazole-2-methanol: A mixture of 5.9 g. (0.024 mole) of2'-anilino-2-hydroxyacetanilide (M.P. 143-150 C.) (prepared fromN-phenyl-o-phenylenediamine and glycolic acid), 5 g. (0.026 mole) ofptoluenesulfonic acid hydrate and 250 ml. of toluene was slowlydistilled over a three hour period. The reaction mixture was cooled,aqueous sodium hydroxide added and the freed base extracted with ether.Solvent removal left a brown solid which was recrystallized to give 4.3g. of 1-phenylbenzimidazole-2-methanol, M.P. 131-132.4 C. (corr.).

Analysis.Calcd. for C H N O: N, 12.49. Found: N, 12.38.

Ethanolic hydrogen chloride was added to a solution of1-phenylbenzimidazole-Z-methanol in acetone. The solid which separatedwas collected and recrystallized from an isopropyl alcohol-acetonemixture to give 1- phenylbenzimidazole-Z-methanol in the form of itshydrochloride salt, colorless needles, M.P. 192-197 C. (corr.). Amixture melting point with the hydrochloride salt of1-phenyl-2methylbenzimidazole 3-oxide showed a marked depression.

Analysis.Calcd. for C H CIN O: N, 10.75. Found: N, 10.53.

1-phenylbenzimidazole-Z-methanol when tested in vitro by standard serialdilution procedures was found to be bacteriostatic and bactericidalagainst Cl. welchii at concentrations of 0.0025 and 0.25 mg. per ml.,respectively. Accordingly, l-phenylbenzimidazole-Z-methanol is useful asa topical disinfectant agent when applied to surfaces infected with theorganism Cl. welchii. It can be prepared for. use by dissolving anacid-addition salt form of the compound in aqueous media.

4 EXAMPLE 2 (a) N-(2,2 dichloroacetyl) 2 nitrodiphenylamine [111; R" isCHCl A solution of 21.4 g. (0.1 mole) of o-nitrodiphenylamine and 29.5g. (0.2 mole) of dichloroacetyl chloride in 30 ml. of toluene wasrefluxed for 24 hours. Ethanol was then added and the mixture cooled tofurnish 22.8 g. of solid, M.P. 143-145 C. The latter was recrystallizedthree times from absolute ethanol to give 10.5 g. of N (2,2dichloroacetyl)-2-nitrodiphenylamine, tan solid, M.P. l52154 C.

Arzalysis.Calcd. for C H Cl N O C, 51.71; H, 3.10; N, 8.61. Found: C,51.80; H, 3.25; N, 8.79.

(b) N (2,2-dichloroacetyl) 2 nitrodiphenylamine was hydrogenatedaccording to the procedure of Example 1, part (b), to give a 57% yieldof l-phenyl-Z-methylbenzimidazole in the form of its hydrochloride salt,M.P. 201-205 0., identical with the product of Example 1, part (b).

EXAMPLE 3 1,2-diphenybenzimidazole 3-oxide [1; R and R are C HN-benzoyl-Z-nitrodiphenylamine (10.29 g.) in ml. of absolute ethanolcontaining 0.034 mole of hydrogen chloride was hydrogenated in thepresence of 100 mg. of platinum oxide. After the uptake of hydrogen hadceased, the reaction mixture was filtered and the filtrate concentratedto remove the solvent. The residue was recrystallized from isopropylalcohol to give 7.84 g. of 1,2- diphenylbenzimidazole 3-oxide in theform of its hydrochloride salt, light pink solid, M.P. 253254 C. (dec.).A sample of the hydrochloride salt was treated with alkali to give thefree base, M.P. 192-195 C. (dec.), when recrystallized from ethylacetate.

Analysis.-Calcd. for C H N O: C, 79.71; H, 4.93; N, 9,79. Found: C,79.98; H, 5.38; N, 9.79.

Similarly, N (p methoxybenzoyl)-2-nitrodiphenylamine can be hydrogenatedto produce 1-phenyl-2-(pmethoxyphenyl)benzimidazole 3-oxide.

EXAMPLE 4 l-methyl 2 phenylbenzimidazole 3 oxide [I; R is CH R is C Hwas prepared by hydrogenating N- benzoyl-N-methyl-2-nitroanilineaccording to the procedure of Example 3, and was obtained in the form ofits hydrochloride salt, M.P. 248250.5 C. (dec.), when recrystallizedfrom absolute ethanol.

Analysis.Calcd. or C H N -HCl: C, 59.17; H, 6.07; N, 15.34. Found: C,58.95; H, 6.08; N, 14.77.

I claim:

1. 1-phenylbenzimidazole-Z-methanol.

References Cited Dalgatov et al.: Chem. Abst., vol, 59, column 10024(1963).

Joseph et al.: Chem. Abst., vol. 57, column 5902 (1962).

HENRY R. JILES, Primary Examiner.

NATALIE TROUSOF, Assistant Examiner.

U.S. Cl. X.R.

